tbuckley/cabot-search huggingface dataset:
Abstract 5832: Utilizing small noncoding RNAs as biomarkers for selinexor treatment in gastric cancer
Authors: Rachel E. Sexton, Amro Aboukameel, Yiwei Li, Husain Y. Khan, Md Hafiz Uddin, Trishyan Kashyap, Yosef Landesman, Anteneh Tesfaye, Asfar S. Azmi
Journal: Cancer Research (2022)

Abstract Gastric cancer is a deadly disease with a low 5-year survival rate of 32%. This disease is characterized by high rates of chemo resistance and late initial detection. We have previously reported that inhibition of nuclear exporter protein Exportin 1 (XPO1/CRM1) with the small molecule inhibitor selinexor (KPT-330) is a viable therapeutic approach in gastric cancer. Inhibition of XPO1 blocks proliferation and suppresses tumor growth through nuclear retention of tumor suppressor proteins such as TP53. Besides nuclear retention, we also demonstrated that XPO1 inhibition leads to a perturbation of cancer specific microRNAs including microRNA-7974 downregulation (miR-7974) and microRNA-129-1-3p upregulation (miR-129-1-3p) within a small RNA sequencing study. In this study we evaluated the role of these microRNAs in gastric cancer perpetuation in respect to their naive functions in five distinct subtypes of gastric cancer. Our results show over-expression of miR-7974 and loss of miR-129-1-3p promotes gastric cancer growth and progression, based on specific subtype of disease. We have further found that the differential expression of these microRNAs leads to gastric cancer cellular changes including cell cycle alterations, upregulation of autophagy processes, chemoresistance and alterations in the cellular framework leading to more invasive phenotypes. Validation with normal gastric epithelial cells revealed these microRNAs are relevant as they are perturbed in gastric cancer as well as the proteins in which they modulate. Finally, we have validated treatment of gastric cancer cells with the XPO1 inhibitor selinexor altered the expression of miR-7974 and miR-129-1-3p differently, based on subtype, as we have previously observed in small RNA sequencing screen, leading to a reversal of the pro-cancerous phenotypes previously observed. In vivo investigation is currently ongoing to identify whether we can capture either miR-7974 or miR-129-1-3p within the serum as further evidence of microRNA perturbation as a predictive biomarker for selinexor efficacy. Citation Format: Rachel E. Sexton, Amro Aboukameel, Yiwei Li, Husain Y. Khan, Md Hafiz Uddin, Trishyan Kashyap, Yosef Landesman, Anteneh Tesfaye, Asfar S. Azmi. Utilizing small noncoding RNAs as biomarkers for selinexor treatment in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5832.
Abstract 3116: Development of bioluminescent PDX models to study metastasis and evaluate therapeutic interventions
Authors: Jonathan Nakashima, Jantzen Sperry, Christophe Pedros, Bianca Carapia, Deborah Yan, Giovanni Rivera, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow
Journal: Cancer Research (2022)

Abstract Metastatic disease continues to be a significant cause of mortality among cancer patients. Despite advancements in patient-derived xenografts (PDXs), translational models of metastasis are lacking. To overcome this challenge, we have developed luciferase tagged PDX cultures and utilized optical imaging to create robust translational in vivo models of metastasis. Here, we show that these models can be implanted orthotopically into common metastatic sites, or injected intravenously or intracardiacally to study spontaneous metastasis. Furthermore, we apply these models in humanized NOG-EXL mice to demonstrate immunophenotypic differences among tumors in different anatomical sites. Citation Format: Jonathan Nakashima, Jantzen Sperry, Christophe Pedros, Bianca Carapia, Deborah Yan, Giovanni Rivera, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Development of bioluminescent PDX models to study metastasis and evaluate therapeutic interventions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3116.
Abstract 5524: AK127, a novel monoclonal antibody (mAb) targeting T cell immunoreceptor (TIGIT)
Authors: Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Chunshan Jin, Na Chen, Dennis Xia, Peng Zhang, Max Wang, Michelle Xia, Baiyong Li
Journal: Cancer Research (2022)

Abstract Introduction: Immune checkpoint blocking antibodies achieved great clinical success, yet a large fraction of cancer patients receive minimum benefit from current immunotherapies targeted PD-1 and CTLA-4. As a new multifunctional immune checkpoint molecule, TIGIT holds promise to become an important cancer immune therapy target. AK127 is a novel humanized immunoglobulin (Ig) G1 monoclonal antibody (mAb) targeting T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT). AK127 binds to TIGIT specifically and blocks the interaction of TIGIT with its ligands, thus relieves immune suppression and promotes anti-tumor immune response. Method: The effect of AK127 on secretion of IL-2 in mixed culture of Jurkat-TIGIT and HT1080-aCD3scFv cells (ELISA) was determined in cellular assays. Binding kinetics of AK127 to C1q, FcγR were measured by Fortebio. ADCC, ADCP and CDC activities were determined in cellular assays. In preclinical in-vivo pharmacology studies, synergistic anti-tumor activity of AK127 and a bi-specific anti-PD1/CTLA4 antibody Cadonilimab (AK104) was investigated in BALB/c-hPD-1/hTIGIT transgenic mice with CT26.WT tumor model. Result: AK127 blocked the immune inhibitory signal mediated by TIGIT, resulting in enhanced IL-2 secretion. AK127 exhibited binding to FcγIa, FcγRIIIa and C1q, and eliciting ADCC, ADCP and CDC. In animal models, both AK104 (0.5 mg/kg) and AK127 (4 mg/kg) significantly inhibited tumor growth. The combination of AK127 and AK104 produced a significantly enhanced anti-tumor effect than either monotherapy, demonstrating the synergistic anti-tumor activity of AK127 combined with AK104. Conclusion: AK127 binds to human TIGIT with high affinity, competitively blocks the binding of TIGIT with its ligand CD155 and CD112, relieves immune suppression in both cellular and animal model systems, and promotes anti-tumor immune response. Citation Format: Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Chunshan Jin, Na Chen, Dennis Xia, Peng Zhang, Max Wang, Michelle Xia, Baiyong Li. AK127, a novel monoclonal antibody (mAb) targeting T cell immunoreceptor (TIGIT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5524.
Abstract 5754: The molecular characteristics of EGFR co-mutations in lung adenocarcinoma
Authors: Yanhong Shang, Hao Zhang, Aiming Zang, Shaohua Yuan, Xiaofang Li, Wenpan Zhang, Ran Huo, Guotao Fang, Zhengyue Dou, Weiwei Liu, Xiao Han, Qi Zhao, Chenglin Xi
Journal: Cancer Research (2022)

Abstract Background: With the development of sensitive next-generation sequencing (NGS) techniques that go beyond the genotyping of specific mutations, detection rates for uncommon mutations have risen clinically. Given this rise in mutation identification, discoveries regarding isolation or coexistent mutations with the EGFR mutation (termed a “complex” mutation) are in “uncharted territory” in terms of their biological impacts on oncogenic pathways and their sensitivity or resistance, to EGFR TKIs. Methods: Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: A cohort of 262 Chinese lung adenocarcinoma patients were recruited. The most common mutated gene was EGFR (63%, 165/262), and followed by TP53 gene (59.2%, 155/262). Beyond single genetic lesions, we found that enriched co-mutations in lung adenocarcinoma were significantly different for TP53 (p &amp;lt; 0.001) and RTK-RAS (p = 0.0012) signaling pathways between the EGFR-positive and EGFR-negative groups. In all EGFR co-mutated patients, the frequency of co-mutation for EGFR/TP53 and the classical EGFR mutation was 106 (64.2%) and 144 (87.3%), respectively. EGFR-only mutations occurred in 50 (30.3%) patients, while co-mutation of EGFR and at least one tumor suppressor gene (TSG) occurred in 84 (50.9%) patients. Patients with EGFR-only mutation had a lower tumor mutational burden (p = 0.026) as compared to patients with only a TSG mutation. Patients with co-mutations of EGFR and at least one TSG also displayed a lower tumor mutational burden, although only a slight difference (p = 0.062) was determined. Conclusions: Profiles of EGFR co-mutational TSGs should be regarded as a unique subgroup for predictive insights in treatments for patients with co-occurrence of somatic EGFR and TSG mutations. To improve predictions related to drug sensitivity in targeted therapies for oncogenes with diverse mutations, our future studies will include publications dedicated to this topic. Citation Format: Yanhong Shang, Hao Zhang, Aiming Zang, Shaohua Yuan, Xiaofang Li, Wenpan Zhang, Ran Huo, Guotao Fang, Zhengyue Dou, Weiwei Liu, Xiao Han, Qi Zhao, Chenglin Xi. The molecular characteristics of EGFR co-mutations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5754.
Abstract 2686: Is ARV7 a regulator of prostate cancer stemness and plasticity
Authors: Tobias Furlan, Florian Handle, Marcus V. Cronauer, Frédéric R. Santer
Journal: Cancer Research (2022)

Abstract Therapy options for advanced and castration-resistant prostate cancer (CRPC) include the use of drugs targeting directly/indirectly the ligand binding domain (LBD) of androgen receptor (AR) such as enzalutamide (Enza) and abiraterone acetate. However, primary or acquired treatment failures are frequently observed and have been associated with the expression of truncated AR variants devoid of the LBD. In particular, the AR variant AR3, also known as ARV7, is detected in over 80% of CRPC specimen and is increasingly expressed in metastatic lesions. In PC models ARV7 expression causes treatment resistance to Enza. Moreover, ARV7 expression leads to increased expression of mesenchymal markers and stem cell signature genes. CDH2 (N-Cadherin) expression is increased by ARV7 binding to regulatory elements in intron 1 of CDH2, which is antagonized by full length (FL) AR. Based on these observations we hypothesize that ARV7 is a marker and regulator of PC stemness and/or plasticity. ARFL or ARV7 mRNA and protein was detected in cell lines and tissue samples by standard procedures including qRT-PCR, RNA in situ hybridization (RISH), immunofluorescence (IF) and western blotting using the monoclonal ARV7 antibody RM7. ARFL or ARV7 stably expressing LNCaP were obtained by lentiviral transduction. LNCaP cells resistant to Enza (LNCaP-Enza) were generated by exposure to increasing concentrations (up to 5 µM) of the drug. Transcriptome analysis in LNCaP-Enza vs. LNCaP was done by RNAseq and Gene Set Enrichment Analysis. ARV7 mRNA was detectable in LNCaP, albeit gene expression was 2.3% - 2.6% of the known ARV7 positive cell lines 22Rv1 and VCaP, respectively. RISH and IF demonstrated that only a fraction (~10%) of LNCaP cells expressed ARV7 mRNA and nuclear localized ARV7 protein. ARV7 mRNA was also detected in isolated epithelial and stromal areas in treatment-naïve prostate cancer specimen by RISH. In contrast, all LNCaP-Enza cells were positive for nuclear ARV7 protein. Transcriptome analysis of LNCaP-Enza cells showed enrichments for published ARV7 gene expression signatures. Insular spots of ARV7 mRNA were detected in treatment-naïve tissue and in isolated cells of the castration-sensitive cell line LNCaP suggesting that these cells could be intrinsically resistant against LBD-targeting drugs and responsible for the failure of various endocrine therapies. This project will further analyze whether this subpopulation possesses stem cell (-like)/plasticity characteristics and whether these are regulated by ARV7. Citation Format: Tobias Furlan, Florian Handle, Marcus V. Cronauer, Frédéric R. Santer. Is ARV7 a regulator of prostate cancer stemness and plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2686.
Abstract 3227: Prognostic role of systemic inflammation in colon and rectal cancer patients: Results from the ColoCare Study
Authors: Jennifer Ose, Tengda Lin, Caroline Himbert, Christy A. Warby, Sheetal Hardikar, Juergen Boehm, Biljana Gigic, Petra Schrotz-King, Martin Schneider, Alexis B. Ulrich, David Shibata, Jane C. Figueiredo, Erin M. Siegel, Christopher I. Li, Adetunji T. Toriola, Cornelia M. Ulrich
Journal: Cancer Research (2022)

Abstract Purpose: Inflammation and angiogenesis are hallmarks of cancer development and progression. No studies have prospectively examined association of angiogenesis-related biomarkers with clinical outcomes in colon and rectal cancer. Patients and Methods: In pre-surgery serum samples from n=426 non-metastatic colorectal cancer (CRC) patients (stage I-III), we investigated associations of inflammatory (e.g., CRP, SAA, sICAM-1, sVCAM-1) and angiogenesis biomarkers (VEGF-A, VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed hazard ratios (HR) and 95% confidence intervals (CI). Analyses were adjusted for age, sex, body mass index, stage, tumor site, and study site, and also exploratory stratified by tumor site (colon vs. rectum). Results: N=65 patients (15%) were deceased and n=59 patients (15%) had a recurrence after a median follow-up of 31 months. Overall, doubling of CRP was associated with a ~24% increase in risk of death (OS: HRlog2: 1.24; 95% CI: 1.11-1.40), a 19% increase in risk of recurrence: HRlog2: 1.19; 95% CI: 1.08-1.32, and a non-statistically-significant 12% increase for DFS HRlog2: 1.12; 95% CI: 0.98-1.28. Similar associations were observed for SAA. Doubling of sICAM-1 was associated with a 4-fold increase in risk of death (OS: HRlog2: 4.05; 95% CI: 2.35-6.98). For the angiogenesis marker VEGF-D, significant heterogeneity was observed in analyses stratified by tumor site: doubling was associated with a 3-fold increase in risk of death for rectal cancer (OS: HR: 3.26; 95% CI: 1.58-6.70) and a 22% reduction in mortality for colon cancer (OS: HR: 0.78; 95% CI: 0.35-1.73; pheterogenity &amp;lt;0.001). Similar heterogeneity was observed in associations of VEGF-D with DFS and risk of recurrence, although not statistically significant (pheterogeneity&amp;lt;0.10). Conclusion: Our data suggest that some biomarkers of inflammation and angiogenesis are prognostic markers for stage I-III CRC patients, with potential differences by tumor site for angiogenesis markers. Citation Format: Jennifer Ose, Tengda Lin, Caroline Himbert, Christy A. Warby, Sheetal Hardikar, Juergen Boehm, Biljana Gigic, Petra Schrotz-King, Martin Schneider, Alexis B. Ulrich, David Shibata, Jane C. Figueiredo, Erin M. Siegel, Christopher I. Li, Adetunji T. Toriola, Cornelia M. Ulrich. Prognostic role of systemic inflammation in colon and rectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3227.
Abstract 2036: Multi-omic dissection of immunotherapy response groups in non-small cell lung cancer (NSCLC)
Authors: Arutha Kulasinghe, James Monkman, Honesty Kim, Aaron Mayer, Ahmed Mehdi, Nicholas Matigian, Marie Cumberbatch, Milan Bhagat, Rahul Ladwa, Scott Mueller, Mark Adams, Ken O'Byrne
Journal: Cancer Research (2022)

Abstract Immunotherapies have led to long term benefits in a subset of non-small cell lung cancer (NSCLC) patients. Developing predictive biomarkers of response to therapy is currently an unmet clinical need. The composition of the cellular content of the tumour microenvironment (TME) is an important characteristic driving treatment resistance. In this study, we utilised spatial transcriptomics methods, including Nanostring digital spatial profiling (DSP) and multiplex IHC, to define the tumour/stroma (compartment) specific proteome and transcriptome from a cohort of 2nd line immunotherapy treated NSCLC patients. We identified by mIHC that CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in immunotherapy resistant tumours (p=0.012). Moreover, IL2 mRNA (p=0.001) in the stromal compartment was significantly increased in patients that were sensitive to ICI therapy, whilst CTLA-4 and IDO-1 were suppressed in responsive patients. Tumour compartment localised CD44 was depleted in the responder group and corresponded inversely with higher stromal expression of one of its ligands, SPP1 (p=0.008). Orthogonal validation of CD44 by multiplex immunofluorescence confirmed both its association with response and localisation to tumour cells rather than immune cell infiltrate. Cox survival analysis showed that tumour compartment CD44 expression was associated with a poorer prognosis (HR=1.61, p=0.01) whilst stromal localisation of CTLA-4 (HR=1.78, p=0.003) and ARG1 (HR=2.37, p=0.01) were associated with poorer outcome. Through a multi-omics approach, we demonstrate the utility of spatial mapping of NSCLC tumours and provide evidence for the role of a number of compartment-specific biomarkers which may aid in identifying those likely to respond to immunotherapy. Citation Format: Arutha Kulasinghe, James Monkman, Honesty Kim, Aaron Mayer, Ahmed Mehdi, Nicholas Matigian, Marie Cumberbatch, Milan Bhagat, Rahul Ladwa, Scott Mueller, Mark Adams, Ken O'Byrne. Multi-omic dissection of immunotherapy response groups in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2036.
Abstract 5100: Analysis of genetic alterations related to hyper-progressive disease after immunotherapy in patients with non-small cell lung cancer
Authors: Xudong Xiang, Hushan Zhang, Deguang Wang, Heng Li, Qing Lei, Qianli Ma
Journal: Cancer Research (2022)

Abstract Background Hyper-progressive disease (HPD) is an unexpected response pattern observed in immune checkpoint therapy, such patients experience a very rapid disease progression (usually progressed seriously in three months). Predictors of HPD are one of the keys to the management of patients receiving immune checkpoint inhibitors. Some factors, such as MDM2/4 amplification, EGFR mutations and old age may be risk factors for HPD, but the results of different studies are inconsistent. Herein, we evaluated the characteristics of MDM2/4 alterations in Chinese patients with NSCLC. Methods The formalin-fixed paraffin-embedded specimens of cancer patients who have underwent next-generation sequencing (NGS) in 3D Medicines, a laboratory accredited by CAP and Clinical Laboratory Improvement Amendments (CLIA) from May 2017 to May 2020, were included in this study. NGS was performed to detect gene mutation, and tumor mutational burden (TMB) measured by a 733 gene panel. PD-L1 expression detected by using Dako PD-L1 IHC 22C3 pharmDx. Results The proportion of MDM2/4 amplification in Chinese NSCLC patients is 0.86%, the proportion of MDM2 and MDM4 amplification in Chinese NSCLC patients were 0.74% and 0.12%. respectively. Further analysis found lower TMB level in patients with MDM2/4 amplification than patients without MDM2/4 amplification (p&amp;lt;0.001). The median TMB level was also found lower in patients with MDM2/4 amplification than without, and higher ratio of patients with TMB-high (defined as TMB≥10mutant/Mb) was displayed in group with MDM2/4 amplification. Conversely, patients with TMB-high showed lower copy number gain in MDM2/4. However, no difference was found in level of PD-L1 expression between patients with and without MDM2/4 amplification. Conclusion HPD happened during ICI treatment in solid tumor with MDM2/4 amplification may associated with lower TMB level, and PD-L1 expression level has limit effect on MDM2/4 alteration related HPD. Citation Format: Xudong Xiang, Hushan Zhang, Deguang Wang, Heng Li, Qing Lei, Qianli Ma. Analysis of genetic alterations related to hyper-progressive disease after immunotherapy in patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5100.
Abstract 5755: Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients
Authors: Feng Gao, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Changsheng Yang
Journal: Cancer Research (2022)

Abstract BACKGROUND: Homologous recombination deficiency (HRD) is associated with tumorigenesis. Therapy directed toward HRD has been approved in breast and ovarian cancer, however, whether there is a chance of benefit for patients with other cancers remains unknown. Herein, we investigated the mutation characteristics of homologous recombination-related (HRR) genes in Chinese patients with sarcoma to explore possible benefit opportunities for sarcoma patients. METHODS: The genetic landscape of HRR genes was assessed in 700 Chinese sarcoma patients with different subtypes including Rhabdomyosarcoma (RMS, n = 67), Liposarcoma (LPS, n = 58), Osteosarcoma (n = 34), Synovial sarcoma (n = 30), Leiomyosarcoma (n = 29), Ewing's sarcoma (EWS, n = 27), Angiosarcoma (n = 20), other rare (n = 375) and unknown subtypes (n = 60). Molecular profiles were performed by using next generation sequencing (NGS)-based Onco Panscan plus࣪ at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments. RESULTS: Among the 700 patients, the overall mutation frequency of HRR genes was 19.0%. Correspond to specific subtypes, the mutation frequency of HRR genes were higher in Leiomyosarcoma (27.6%, 8/29), Angiosarcoma (25.0%, 5/20) and LPS (17.2%, 10/58) compared with RMS (14.9%, 10/67), Osteosarcoma (14.7%, 5/34), Synovial sarcoma (13.3%, 4/30) and EWS (3.7%, 1/27). ATRX was the most commonly mutated gene (5.1%, n = 36) and was preferentially identified in Leiomyosarcoma (10.3%) and Angiosarcoma. (10.0%), followed by ARID1A (3.1%, n = 22), ATM (2.1%, n = 15) and FANCA/C/D2/E/F/G/L (1.7%, n = 12). The median tumor mutational burden (TMB) was 2.35 in patients with HRD and 0.94 in patients without HRD. Although BRCA1 and BRCA2 mutations were less common overall (1.1% and 0.7%), a significant proportion of BRCA1 and BRCA2 mutations was found in Angiosarcoma, Liposarcoma and Leiomyosarcoma (5.0%, 3.4% and 3.4%, respectively). CONCLUSION: Our results reported the genetic landscape of HRR genes in Chinese sarcoma patients, providing a reference for the clinical application of PARP inhibitors. Citation Format: Feng Gao, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Changsheng Yang. Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5755.